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- the movement of gas between the environment & the blood
- it involves
- 1. transport between the atmosphere & the alveolus (breathing)
- 2. diffusion across the alveolar/capillary membranes into the blood
Fick’s Law of Diffusion
- states that the volume of a gas that passes through a barrier is a function of the area of the barrier divided by its thickness * the diffusion constant * the partial pressure gradient for the gas across the membrane (ΔP)
- Vgas ∝ A/T * D * (P1–P2)
- the gasses we’re interested = O2 & CO2
Diffusion Coefficient (Constant)
- is a function of the solubility of the gas in question divided by the square root of its molecular weight
- D ∝ Sol / √MW
- units = mL/min * mmHg
- it’s directly proportional to the solubility of a gas & inversely proportional to the square of its molecular weight
- a gas will dissolve in a liquid in proportion to its partial pressure over the liquid
- the actual amount that dissolves = the solubility coefficient * partial pressure
Which is more soluble in aqueous solution, CO2 or O2?
- CO2 is ~ 20x more soluble than O2
- therefore it diffuses more rapidly EVEN THOUGH it has a higher MW (CO2 = 28 Da, O2 = 16 Da)
Solubility of O2 & CO2 in Plasma
- [O2]diss = 0.003 mL O2 / dL / mmHg * PO2
- [O2]diss = 0.06 mL CO2 / dL / mmHg * PO2
- 0.003 mL of O2 will dissolve in a deciliter of aqueous solution per mmHg
- would multiply that times the partial pressure of oxygen in the blood if you want to find out HOW MUCH O2 is dissolved in the blood
At what rates do CO2 & O2 diffuse across alveolar/capillary membrane?
- both gasses diffuse at similar rates
- although CO2 is more soluble, the driving force for diffusion (ΔP) is GREATER for O2 than CO2
- the partial pressure difference for O2 across the alveolar/capillary barrier is ~60 mmHg
- for CO2 it’s only 6 mmHg
What is capillary transit time for RBCs in the pulmonary system?
- 0.75 seconds - gas exchange occurs VERY quickly
- equilibration of O2 & CO2 occurs in ~ 0.3 sec so there is ample time for gas equilibration to occur
What factors can alter transit time?
- exercise REDUCES the transit time
- however there is still adequate reserve to fully exchange the gases
What happens to gas exchange at high altitudes?
- at high altitudes there’s a lower PatmO2
- this reduces the alveolar-capillary partial pressure gradient for oxygen, meaning there might not be
- enough DRIVING FORCE to fully load the blood w/ O2 during normal transit time
How would you measure the diffusion capacity of the lung?
- using Carbon Monoxide (CO)
- a subject breathes a low CO-air mixture
- PACO is high
- CO would normally bind STRONGLY to hemoglobin
- however b/c capillary (RBC) PCO fails to reach alveolar PCO, the uptake of CO must be diffusion limited
How would you measure the perfusion limitations of gas exchange?
- using Nitrous Oxide (N2O)
- N2O doesn’t combine w/ hemoglobin, therefore as N2O exchanges across the alveolar-capillary barrier, the PN2O rises rapidly & reaches that of the alveolar gas (PAN2O) only 1/10 of the way along the capillary
- the amount of N2O taken up by the blood depends upon the blood flow (how fast it passes through the capillaries) & not on the diffusion properties of the barrier – it is perfusion LIMITED
What does it mean to be perfusion limited?
- it means that the amount of gas that can be transferred into the blood is dependent on HOW MUCH blood passes through the capillaries
- more blood → more gas (high Pgas)
- *oxygen is perfusion limited: get more oxygen in blood by having a higher perfusion rate
What is true about both O2 & CO2?
- they both reach equilibrium between blood & alveolar partial pressures
- they are perfusion LIMITED in a healthy individual
What happens to the equilibrium between blood & alveolar partial pressures in pulmonary diseases that increase the thickness of alveolar-capillary walls?
- the diffusion coefficient DECREASES - O2 might defuse more slowly
- the PO2 at the end of the capillary may be BELOW the PAO2 (equilibrium isn’t reached)
- less O2 makes it into the blood*
- eg. COPD (destroys pulmonary capillaries), diffuse fibrosis of pulmonary parenchyma, or loss of functional tissue from a tumor or surgery
What equation can be used to calculate alveolar oxygen (PO2)?
- the Alveolar Gas Equation
- PAO2 = PIO2 – (PaCO2 / 0.8)
- PAO2: alveolar oxygen
- PIO2: partial pressure of O2 in inspired (tracheal) air (~160 mmHg)
- PaCO2: the arterial PCO2
- 0.8: the respiratory exchange ratio (volume of CO2 expired per volume of O2 inspired)
- PAO2 = 143 – (40 / 0.8) = 103 mmHg
- alveolar arterial difference in O2
- in healthy individuals this is ~4 mmHg
- is the difference between alveolar gas & mixed arterial blood even after complete equilibration
- normal alveolar PO2 ~ 104 mmHg, but arterial PO2 is ~ 100 mmHg
What causes A-aDO2?
an imperfect balance between ventilation & perfusion of the lung - bronchial circulation especially
What happens to A-aDO2 in normal subjects with age (over time)?
- it INCREASES w/ both age & loss of lung compliance
- over 30, the A-aDO2 = age * 0.3 mmHg
What would an abnormally high A-aDO2 indicate?
- a pathological problem in which gas exchange is compromised
- eg. emphysema, pneumonia, asthma, etc.
- usually indicates a difficulty of getting O2 from the alveoli into the blood stream
Low O2 Solubility Causes a Problem
- we want to carry O2 from the lungs → tissue
- w/ an arterial PO2 of 104 mmHg, dissolved O2 is low (0.003 * 104 = 0.312 mL/dL) ~ 1.5% of the total content
- 0.312 mL/dL is the maximum amount of oxygen we can dissolve in water at alveolar pressure
What is an adaptation that increases oxygen-carrying capacity, seeing as how plasma (aq. soln) can only carry 0.312 mL/dL?
- Hemoglobin (Hb) carries the remaining O2
- Hb has 4 polypeptide chains, each containing a heme group (porphyrin ring w/ a ferrous ion)
- each heme group binds one O2 molecule
- therefore Hb can sequentially bind up to 4 O2
What does adding Hb to a solution do in terms of amount of O2 able to diffuse into that solution?
- adding Hb (to side B) lowers PO2 as oxygen binds to the Hb (it becomes part of the protein - no longer contributes to the PO2 which is only made up of diffused O2)
- free, dissolved oxygen from the other side (A) now diffuses into side B, down its gradient
- total oxygen is the same in the solutions but the PO2 is much lower → the overall oxygen content on side B is GREATER than on side A
Different Species of Hb Binding O2
- Hb = apohemoglobin → HbO2 → HbO4 → HBO6 → HbO8 = fully saturated hemoglobin
- as we raise partial pressure of O2 (put more free O2 into solution), O2 is driven to bind w/ Hb
- gives us saturation of Hb as a function of free O2 (PO2)
- at PO2 normally seen in arterial blood (100 mmHg), Hb is ALMOST 100% saturated
- this means that as blood passes through alveolar capillaries, it’s both saturating its Hb ~100% & carrying a PO2 of 100 mmHg, almost = to PAO2
How saturated is Hb at a PO2 of 40 mmHg (level in venous blood after exchange has occurred w/ cells in systemic tissues)?
- means that 1 O2 is unloaded from e/a heme from Hb as the PO2 drops from 100 → 40 mmHg
- this is how blood returns to the heart - means we’re really only loading 1 O2 onto each Hb during re-oxygenation
- *other 3 represent a RESERVE capacity
Dissolved O2 in Arterial Blood
- 0.003 mL O2/dL/mmHg * 100 mmHg = 0.3 mL/O2/dL
- there is 0.3 mL dissolved O2 per deciliter of blood
Hemoglobin-bound O2 in Arterial Blood
- when Hb is 100% saturated, 1gm of Hb can bind 1.34 mL of O2
- about 15gm Hb is in e/a dL of blood
- assume 97.5% saturation
- 1.34 mL/gm * 15 gm/dL * 0.975 = 19.6 mL O2 / dL
Total O2 Content in Arterial Blood
- consists of both dissolved & Hb bound O2
- 0.3 mL/dL + 19.6 mL/dL = 19.9 mL O2/dL blood
- ~20 mL of oxygen per deciliter of arterial blood
Why is it critical for some O2 to be dissolved in arterial blood?
- dissolved oxygen represents only ~ 1.5% of the total content in arterial blood; the other 98.5% is bound to Hb
- dissolved O2 is critical b/c it maintains the PO2 necessary to keep the Hb saturated, & because only FREE O2 can diffuse across cell membranes
- also w/o it the PO2 would drop to 0 mmHg & the Hb would immediately unload its O2
Dissolved O2 in Venous Blood
- 0.003 mL O2/dL/mmHg * 40 mmHg = 0.12 mL/O2/dL
- there is 0.3mL dissolved O2 per deciliter of blood
Hemoglobin-bound O2 in Venous Blood
- hemoglobin is 75% saturated in venous blood
- 1.34 mL O2 / gm * 15 gm/dL * 0.75 = 15.075 mL O2/dL
Total O2 Content in Venous Blood
- consists of both dissolved & Hb bound O2
- 0.12 mL/dL + 15 mL/dL = 15.2 mL O2/dL blood
- ~15 mL of oxygen per deciliter of venous blood
- therefore, the amount of O2 delivered to resting tissue per dL blood =
- 19.9 – 15.2 = 4.7 mL O2 per dL of perfusion
For every deciliter of blood to a tissue at rest, how much O2 is released to that tissue?
~5 mL, most of it coming from the hemoglobin
- oxygen saturation (SaO2) of arterial blood can be non-invasively monitored using a pulse oximeter which has a probe that can be attached to the finger or ear lobe where arterial blood pulses
- light at two wavelengths (660 & 940 nm) is shined through the tissue
- OxyHb has a greater absorption than deoxyHb at 940nm
- DeoxyHb has greater absorption than oxyHb at 660nm
- the absorbance of light at both wavelengths is monitored during the pulses of blood flow & is used to compute O2 saturation
What 4 things happen to an exercising muscle tissue?
- 1. it gets warmer
- 2. its metabolic rate increases
- 3. its PCO2 increases locally
- 4. its pH decreases (from lactic acid production)
- these last 3 decrease Hb’s affinity for O2 via allosterism
- RBCs entering this tissue will also get warmer & increase their metabolic rate (no mitochondria though, can only metabolize via glycolysis)
- ↑ glycolysis → ↑ 2,3-BPG
binding a molecule at one site affects a different molecule’s binding ability at a DIFFERENT site
How does temperature affect the binding of O2 to hemoglobin?
- high temperatures DECREASE O2’s affinity for Hb thus releasing more O2 at a given PO2
- higher temperatures occur in actively working muscles (up to ~ 40oC) & w/ fever
- temperature increases the kinetic E of system which basically causes a dissociation of bound O2 at higher temps
- lower temperatures INCREASE the binding affinity of O2 to Hb
- this effect may be related to small shifts in AA side chain pK values that cause a conformational change in Hb
- can see the higher temperature curve has LESS Hb saturated w/ O2 at any given PO2
How does pH affect the binding of O2 to hemoglobin?
- respiratory acidosis shifts the curve to the
- right – this is called the Bohr effect
- ↑ metabolism in active muscle generates acid from increased CO2 & lactic acid production
- these enter the RBCs & affect titratable groups on Hb → a decrease in O2 affinity
- (pH-induced changes in Hb are independent of PCO2)
How do changes in PCO2 affect the binding of O2 to hemoglobin?
- increasing PCO2 produces a small shift of the curve to the right independently of pH changes
- CO2 binds to free amino groups, especially the N-terminal amino groups of the four Hb chains, & generates carbamino groups
- CO2 + Hb-NH2 = Hb-NH-COO-
How do changes in 2,3-BPG (DPG) affect the binding of O2 to hemoglobin?
- 2,3-diphosphoglycerate, a glycolytic metabolite normally binds in a 1:1 stoichiometry to Hb
- stimulation of glycolysis in exercise increases 2,3-DPG levels, which leads to a decreased affinity of Hb for O2
Carbon Monoxide (CO) Poisoning
- CO, a product of incomplete combustion of carbonaceous materials, binds to the heme group of Hb with 250x the affinity of oxygen & therefore competitively inhibits O2 binding
- CO forms carboxyhemoglobin
- CO shifts the Hb-O2 dissociation curve slightly to the LEFT, DECREASING O2 release from Hb for what O2 molecules actually bind to Hb
- Nitric oxide, NO, has similar effects
Fetal Hemoglobin (HbF)
- erythrocytes in the developing fetus contain HbF
- HbF has a HIGHER affinity for O2 than adult Hb (HbA)
- this facilitates the extraction by the fetus of maternal blood at the placenta
- a newborn’s blood has ~ = amounts of HbF & HbA
- by the end of the 1st year HbF falls to only 1-2% of total Hb
- normal Hb can have its heme ferrous ion (Fe++) oxidized into a ferric (Fe+++) ion by various drugs or chemicals (eg. nitrites, sulfonamides)
- the resulting molecule is methemoglobin (Met-Hb) which CANNOT bind O2
- in the RBC the enzyme Met-Hb Reductase can reduce Met-Hb back to normal Hb
- therefore, only about 1.5% of Hb is in the Met-Hb state
What are the 3 forms through which CO2 can be transported in the blood (from the tissues where it’s formed back to the lungs for disposal)?
- 1. dissolved CO2 (~6%): what gives PCO2 of 46 mmHg in venous blood
- solubility = 0.06 mL CO2/dL / mmHg (CO2 has limited water solubility)
2. bicarbonate (~70%): mostly formed in RBCs by carbonic anhydrase
- 3. carbamino compounds (~24%): CO2 reacts w/ free amines on proteins (predominantly those of Hb)
- CO2 + Protein-NH2 → Protein-NH-COO- + H+
- accelerates the combination of CO2 & water to form carbonic acid, H2CO3
- converts CO2 + H2O → H2CO3
- is strictly intracellular
Where is most bicarbonate in the body synthesized?
- ~ 65% us made in erythrocytes containing carbonic anhydrase
- once formed carbonic acid quickly dissociates into H+ & HCO3- (H2CO3 → H+ + HCO3-)
- can be carried in both RBCs & plasma
What transporter is responsible for moving newly formed HCO3- out of Red Blood Cells?
- AE1, the Cl–HCO3- exchanger
- it transports newly formed HCO3- out of the red blood cell
- this PROMOTES the formation of more HCO3-
What takes care of the acid environment created by the dissociation of H2CO3 into H+ & HCO3-?
- Intracellularly: Hemoglobin
- Extracellularly: Plasma Proteins
- they buffer the H+ produced during HCO3- formation
What happens if HCO3- is made outside an RBC, say in the plasma?
- ~5% of CO2 does form HCO3- in the plasma
- b/c there is no carbonic anhydrase in the plasma, it has a lower buffering capacity than the RBCs
- the build-up of an acidic environment is less easily dealt with
- ~21% of CO2 entering the capillaries forms carbamino compounds by reacting w/ free amine groups on proteins
- most of this occurs inside RBCs & involves Hb
- Hb concentration inside RBCs is ~33 g/dL
- plasma proteins ~7 gm/dL
Which forms carbamino compounds more rapidly, Hemoglobin or Plasma proteins?
- Hb forms carbamino compounds more rapidly than plasma proteins
- its higher buffering capacity allows it to more readily bind H+ ions generated by carbamino formation
- carbaminohemoglobic can still bind O2 in free heme groupds
What induces rapid formation of carbamino compounds?
- the loss of bound O2 in the systemic capillaries
- this causes Hb to form carbamino compounds even more rapidly
- is a “reverse” of the CO2-induced Bohr effect
- oxygenation of blood DECREASES carbamino-Hb formation
- at the tissue level decreased PO2 allows Hb to take up more CO2 & H+ ions
- in the alveolus increasing PO2 facilitates the release of Hb-bound CO2
- the CO2 equilibrium curve is essentially linear in the physiological range (30-50 mmHg)
- thus, increased PCO2 → a proportional increase in CO2 carried in all forms
- CO2 binds less in the presence of high O2 saturation; helps UNLOAD CO2 at the alveoli
Which blood can carry more more CO2, venous or arterial blood?
- venous blood can carry more CO2 than arterial blood
Measuring O2 & CO2 in Blood Samples
- a sample is drawn from a vessel into a heparinized syringe which is then sealed
- PO2 is measured using an electrode & reported in mmHg
- PCO2 is also measured using an electrode which directly reports mmHg
- measurement of total CO2 includes dissolved CO2 + carbonic acid & bicarbonate
- PaCO2 is used to indicate PACO2
- can also be used to determine [Hb] & pH
measures CO2 in exhaled gas
What factors affect a measured Capnography value?
- 1. cardiac output
- 2. pulmonary perfusion
- (CO2 transport is dependent on these)
- 3. ventilation
- 4. effect of lung diseases
- 5. drug therapy
- 6. body temperature
ETCO2 (End Tidal CO2)
- is typically slightly less than PaCO2 (30-43 mmHg)
- an increased ETCO2 may be caused by hypOventilation, increased muscle activity, increased body temperature
- decreased ETCO2 may be caused by hypErventilation, decreased muscle activity, or hypOthermia